+ MODEL Journal of Microbiology, Immunology and Infection (2016) xx,1e6

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REVIEW ARTICLE Modulation of -related apoptosis-inducing ligand (TRAIL)-mediated apoptosis by Helicobacter pylori in immune pathogenesis of gastric mucosal damage Hwei-Fang Tsai a,b, Ping-Ning Hsu c,d,* a Department of Internal Medicine, Taipei Medical University Shuang Ho Hospital, Taipei, Taiwan b Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan c Graduate Institute of Immunology, College of Medicine, National Taiwan University, Taipei, Taiwan d Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan

Received 1 March 2015; received in revised form 20 December 2015; accepted 17 January 2016 Available online ---

KEYWORDS Abstract Helicobacter pylori infection is associated with chronic gastritis, peptic ulcer, apoptosis; gastric carcinoma, and gastric mucosa-associated lymphoid tissue lymphomas. Apoptosis ; induced by microbial infections is implicated in the pathogenesis of H. pylori infection. FLIP; Enhanced gastric epithelial cell apoptosis during H. pylori infection was suggested to play Helicobacter pylori; an important role in the pathogenesis of chronic gastritis and gastric pathology. In addition TRAIL to directly triggering apoptosis, H. pylori induces sensitivity to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis in gastric epithelial cells. Human gastric epithelial cells sensitized to H. pylori confer susceptibility to TRAIL-mediated apoptosis via modulation of death-receptor signaling. The induction of TRAIL sensitivity by H. pylori is dependent upon the activation of caspase-8 and its downstream pathway. H. pylori induces caspase-8 activation via enhanced assembly of the TRAIL death-inducing signaling complex through downregulation of cellular FLICE-inhibitory protein. Moreover, H. pylori infection in- duces infiltration of T lymphocytes and triggers inflammation to augment apoptosis. In H. py- lori infection, significant increases in CCR6þ CD3þ T cell infiltration in the gastric mucosa was observed, and the CCR6 ligand, CCL20 chemokine, was selectively expressed in inflamed gastric tissues. These mechanisms initiate chemokine-mediated T lymphocyte trafficking into inflamed epithelium and induce mucosal injury during Helicobacter infection. This article will review recent findings on the interactions of H. pylori with host-epithelial signaling pathways and events involved in the initiation of gastric pathology, including gastric inflammation and mucosal damage.

* Corresponding author. Graduate Institute of Immunology, College of Medicine, National Taiwan University, 1 Jen-Ai Road, Section 1, Taipei 100, Taiwan. E-mail address: [email protected] (P.-N. Hsu). http://dx.doi.org/10.1016/j.jmii.2016.01.002 1684-1182/Copyright ª 2016, Taiwan Society of Microbiology. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Please cite this article in press as: Tsai H-F, Hsu P-N, Modulation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)- mediated apoptosis by Helicobacter pylori in immune pathogenesis of gastric mucosal damage, Journal of Microbiology, Immunology and Infection (2016), http://dx.doi.org/10.1016/j.jmii.2016.01.002 + MODEL 2 H.-F. Tsai, P.-N. Hsu

Copyright ª 2016, Taiwan Society of Microbiology. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by- nc-nd/4.0/).

Helicobacter pylori infection and apoptosis in homology with FasL that is capable of inducing apoptosis in 22,23 gastric epithelial cells a variety of transformed cell lines in vitro, but usually not in normal primary cells. T cells can kill target cells via TRAIL/TRAIL-receptor interaction,24,25 indicating that Helicobacter pylori is a common human pathogen that in- TRAIL might serve as a cytotoxic effector molecule in fects over half of the world population and is associated activated T cells in vivo. These findings suggested that with duodenal and peptic ulcer diseases. The clinical con- TRAIL/TRAIL-receptor interaction is involved in the inter- sequences range from asymptomatic gastritis to peptic ul- action between infiltrating T cells and gastric epithelium ceration and gastric malignancy.1,2 The outcome of the during H. pylori gastritis. Recent studies demonstrated that infection is determined by interactions among H. pylori human gastric epithelial cells sensitized to H. pylori confer virulence factors, host gastric mucosal factors, and the susceptibility to TRAIL-mediated apoptosis, suggesting a environment. However, the mechanisms by which host role for immune-mediated apoptosis in gastric epithelial factors cause disease remain unclear. Apoptosis induced by cells by infiltrating T cells during Helicobacter infec- microbial infections is implicated in the pathogenesis of H. tion.6,14,26 The induction of TRAIL sensitivity by H. pylori is pylori infection, and enhanced gastric epithelial cell dependent upon bacterial cell contact, irrespective of apoptosis during H. pylori infection was suggested to play expression of H. pylori virulent factors.6 an important role in the pathogenesis of chronic gastritis e TRAIL-induced apoptosis occurs through a caspase and gastric pathology.3 7 Direct cytotoxicity, as well as signaling cascade, and resistance to TRAIL is controlled by inflammatory responses, occurs in gastric mucosa e intracellular regulators of apoptosis. Crosslinking of the cells.5,8 10 H. pylori vacuolating (VacA) toxin induces TRAIL receptors leads to the formation of a death-inducing gastric epithelial cell apoptosis, but cytotoxin-associated signaling complex (DISC)27 assembled by the death-adaptor gene A (CagA) attenuates apoptosis in gastric epithelial protein Fas-associated death-domain protein (FADD) and cells. Bacterial virulent factors may contribute directly to e caspase-8 and -10.28 30 Activated caspase-8 is generated apoptosis in epithelial cells, whereas the induction of after DISC formation, and initiates apoptosis-inducing cas- sensitivity to death-receptor mediated apoptosis by H. py- pase signaling cascade. Previous studies demonstrated that lori is independent of H. pylori virulent factors VacA and TRAIL-induced apoptosis could be enhanced by Heli- CagA,6 suggesting that immune factors, in addition to cobacter and hepatitis C virus core proteins6,31; however, bacterial factors, are also important in determining the the mechanisms leading to microbe-induced TRAIL sensi- degree of gastric mucosa damage during H. pylori infection. tivity remain unclear. H. pylori-induced sensitivity to It was demonstrated that T helper type 1 (Th1) cells e TRAIL-mediated apoptosis in gastric epithelial cells is selectively increased during H. pylori infection.11 14 Th1 cy- dependent upon activation of the caspase-8 downstream tokines, such as gamma (IFN-g) and tumor necrosis pathway for conveyance of death signals to mitochondria, factor alpha (TNF-a), can increase the release of proin- resulting in activation of mitochondrial pathways and flammatory , augmenting apoptosis induced by H. removing resistance to apoptosis. H. pylori also induces pylori.10 H. pylori infection could also induce gastric mucosa sensitivity to TRAIL-mediated apoptosis by regulation of damage by increasing expression of Fas in gastric epithelial FLICE-inhibitory protein (FLIP) and assembly of DISC, which cells, leading to gastric epithelial cell apoptosis through Fas/ initiates caspase activation26 and promotes apoptosis, (FasL) interaction with infiltrating T cells.9,15 These thereby providing insight into the pathogenesis of gastric findings suggest a role for immune-mediated apoptosis of damage during Helicobacter infection (Figure 1). Modula- gastric epithelial cells during H. pylori infection. Additionally, tion of host-cell apoptosis by bacterial interaction adds a H. pylori directly triggers cell death by cytotoxins after new dimension to immune pathogenesis associated with interacting with gastric epithelial cells.16,17 Furthermore, H. Helicobacter infection. pylori translocates CagA into gastric epithelial cells by Type IV secretion, inducing intracellular protein phosphorylation and dysregulating signal transduction pathways within host cells.18e21 In addition to directly triggering apoptosis, it is Chemokine-mediated lymphocyte trafficking possible that H. pylori induces sensitivity to apoptosis in of T lymphocytes in gastric inflammation gastric epithelial cells via modulation of apoptosis signaling. during H. pylori infection

H. pylori modulate tumor necrosis factor- During H. pylori infection, the degree of apoptosis induced in the stomach is affected by the inflammatory response. H. related apoptosis-inducing ligand (TRAIL)- pylori infection induces a T cell response, as well as a mediated apoptosis in gastric epithelial cells number of inflammatory mediators, including cytokines and .7,11,14,32 These infiltrating T cells can then TNF-related apoptosis-inducing ligand (TRAIL; also called target and destroy gastric cells via TRAIL/TRAIL-receptor Apo2L) is a novel TNF superfamily member with strong interaction. In addition to its role in inducing apoptosis by

Please cite this article in press as: Tsai H-F, Hsu P-N, Modulation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)- mediated apoptosis by Helicobacter pylori in immune pathogenesis of gastric mucosal damage, Journal of Microbiology, Immunology and Infection (2016), http://dx.doi.org/10.1016/j.jmii.2016.01.002 + MODEL Immune pathogenesis in Helicobacter infection 3

Figure 1. Helicobacter pylori modulates TRAIL-mediated apoptosis in gastric epithelial cells. H. pylori enhances assembly of TRAIL death inducing signaling complex (DISC) through downregulation of FLIP after TRAIL engagement, to activate caspase 8 cleavage, and to convey the death signal to mitochondria via cleavage of Bid, leading to activation of mitochondrial pathway and breaking the apoptosis resistance. DED Z death effector domain; DD Z death domain; DR4 Z death receptor 4; DR5 Z death receptor 5; FADD Z Fas-associated death-domain protein; FLIP Z FLICE-inhibitory protein; TRAIL Z tumor necrosis factor-related apoptosis-inducing ligand. binding to death receptors, TRAIL can directly stimulate pylorieassociated diseases. These results indicate that im- T cells by binding to TRAIL receptors and transducing a mune reaction and inflammation mediators associated with H. reverse signal to T cells in conjunction with T cell receptor pylori plays an important role in the pathogenesis of H. pylori- engagement, resulting in T cell proliferation and augment- associated diseases. Among T cells responding to H. pylori ing IFN-g secretion.33e35 Therefore, these results support a infection, gastric-infiltrating T cells are mostly functional role of TRAIL in H. pylori-induced apoptosis. CD45ROþCD69þCD4þT cells, indicating an accumulation of Moreover, the degree of apoptosis during H. pylori infection activated memory CD4þ T cells during Helicobacter infec- may also be linked to the associated inflammatory response. tion.14 Recent reports indicated that Th1 and Th17 responses Therefore, in addition to H. pylori virulence, mucosal were induced during H. pylori infection,11,14,32 and that levels damage may also be affected by the inflammatory response of IFN-g and TNF-a increased in the gastric mucosa during H. induced by H. pylori within the gastric epithelium. pylori infection, augmenting H. pylori-induced Inflammation of the gastric mucosa develops in response to apoptosis.5,6,10 These results suggest a role for immune- host immune reaction against pathogens. The stimulation of mediated apoptosis in gastric epithelial cells by infiltrating epithelial cells by H. pylori contributes to and T cells during Helicobacter infection. However, the induction lymphocyte recruitment. As described, the features of H. of immune responses and the immunopathogenic mecha- pylori-induced inflammatory immune response are orches- nism(s) of mucosal inflammation during H. pylori infections trated by sequential elaboration of proinflammatory cyto- remain unclear, with chemokines thought to play an impor- kines, including (IL)-10, IFN-g,TNF-a, and IL-1b. tant role in this process.36,37 Chemokines are involved in acute Accordingly, factors involved in regulating responses and chronic inflammatory processes by attracting neutro- may confer susceptibility to or protection against H. phils, , and T cells to the site of inflammation via

Please cite this article in press as: Tsai H-F, Hsu P-N, Modulation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)- mediated apoptosis by Helicobacter pylori in immune pathogenesis of gastric mucosal damage, Journal of Microbiology, Immunology and Infection (2016), http://dx.doi.org/10.1016/j.jmii.2016.01.002 + MODEL 4 H.-F. Tsai, P.-N. Hsu

Figure 2. Immune pathogenesis of gastric mucosa damage in Helicobacter pylori infection. In the absence of H. pylori infection, there are very few infiltrating T cells recruited into the gastric mucosa. When T cells interact with human gastric epithelial cells in the presence of H. pylori infection, there are increased CCR6þ activated T cells infiltrated into gastric mucosa via CCL20 induced by H. pylori. The infiltrated activated T cells are recruited into gastric mucosa via CCR6, and then induce apoptosis to gastric epithelial cells via TRAIL/TRAIL receptor interaction. CagA Z cytotoxin-associated gene A; DR4 Z death receptor 4; DR5 Z death receptor 5; TRAIL Z tumor necrosis factor-related apoptosis-inducing ligand. their corresponding chemokine receptors.38,39 Recent reports activation of caspase-8 and its downstream pathway via showed that there are specific chemokines that mediate the enhanced assembly of the TRAIL DISC through down- homing of lymphocytes in the intestines,37,40 suggesting that regulation of cellular FLIP. The degree of mucosal damage some chemokines may be involved in lymphocyte trafficking is also affected by the inflammatory response induced by H. in the gut. A set of proinflammatory chemokines are also pylori within the gastric epithelium. These results suggest a involved in H. pylori gastritis: Gro-a, IL-8, RANTES, IFN-g- role for immune-mediated apoptosis and mucosa damage inducible protein-10 (IP-10; CXCL10), a monokine induced by by infiltrating T cells during Helicobacter infection. In IFN-g (MIG, CXCL11), and CCL20 (MIP-3a/LARC/ conclusion, H. pylori enhances susceptibility of gastric exodus).14,41,42 It was demonstrated that the gastrointestinal epithelial cells to TRAIL-mediated apoptosis via modulation epithelium senses invading microorganisms and produces cy- of death-receptor signaling. Modulation of host-cell tokines/chemokines that attract lymphocytes and dendritic apoptosis by bacterial interaction adds a new dimension cells to the site of inflammation.43 Recently, it was reported to the immune pathogenesis associated with chronic Heli- that CCR6 mediates dendritic cell localization, lymphocyte cobacter infection. homeostasis, and immune responses in mucosal tissue.44 CCR6, a specific b- for CCL20, is selec- Conflicts of interest tively expressed on dendritic cells and some memory Tcells,43,45,46 and may play a role in chemokine-mediated The authors declare no conflicts of interest. lymphocyte trafficking during gastric inflammation. Addi- tionally, CCL20, the ligand of CCR6, is abundantly expressed in mouse and human inflammatory enteric mucosa,47 and CCL20 Acknowledgments production was upregulated in response to H. pylori in gastric epithelial cells when there was stimulation by the proin- 14,48e50 This work was supported by grants from the National Sci- flammatory cytokines IL-1b and TNF-a. These results ence Council, Taiwan (NSC98-3112-B-002-047, NSC101- implicated the interaction between CCL20 and CCR6 in 2320-B-038-019-, and NSC 101-2321-B-002-008-). recruiting CD45ROþ memory T cells to sites of inflammation in the gastric mucosa during Helicobacter infection (Figure 2).14 References Conclusion 1. Parsonnet J, Friedman GD, Vandersteen DG, Chang Y, Vogelman JH, Orentreich N, et al. Helicobacter pylori infection Human gastric epithelial cells sensitized to H. pylori confer and risk of gastric carcinoma. N Engl J Med 1994;325:1127e31. susceptibility to TRAIL-mediated apoptosis, and the induc- 2. Peek RMJ, Blaser MJ. Helicobacter pylori and gastrointestinal tion of TRAIL sensitivity by H. pylori is dependent upon the tract adenocarcinomas. Nat Rev Cancer 2002;2:28e37.

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